The associations of autofluorescence changes in age-related macular degeneration (AMD) and Stargardts Dystrophy along with new understanding of role of different photochemistries in creation and modification of the fluorescent bisretinoids support the hypothesis that rising steady-state levels of bisretinoids within the retinal pigment epithelium (RPE) and photoreceptors induce chronic stress and cellular injury. Importantly bisretinoids are created by high all-trans-retinal levels during periods of high rod rhodopsin activation rates and dependent on cumulative retinal spectral irradiance. We have modeled the effects of retinal spectral irradiance on rod activation and bisretinoid production and subsequent photochemical oxidation within RPE granules during normal aging at different cumulative ambient light exposures. Significant decreases in green-light dependent bisretinoid production with advancing age are more than offset by larger reductions in violet-blue photochemical oxidation of bisretinoids within the RPE granules predicted by our model to lead to an almost linear increase unoxidized bisretinoid fluorescence with age. Delori observed this age-dependence in the autofluorescence of normal subjects as a function of age. Over a broad range of cumulative bright daylight exposures, our model predicts similar bisretinoid levels (fluorescence) dependent mainly on the spectral transmittance of the human lens which yellows with age. We propose that at normal retinal irradiances the violet light detoxifies the accumulated bisretinoids in RPE granules that were largely created in the rods during periods of bright daylight exposure, but this detoxification rate relative to the bisretinoid production rate declines as the lens yellows with age. In the normal population, the levels of unoxidized bisretionoids with the RPE only reach cytotoxic levels at advanced ages associated with increasing incidence of age-related macular maculopathy. In Stargardts the increased bisretinoid production in the photoreceptor outer segments due to ABCA4 dysfunction causes cytotoxic levels to be achieved earlier in life and perhaps more dependent of cumulative light exposure. We proposed in 2004, the wearing of a simple vermillion sunglass whenever in bright daylight would selectively reduce rod activation and bisretinoid production. Such low-cost disease prevention strategy might have significant impact in slowing or preventing disease progression in early Stargardt's and might prevent age-related maculopathy by dramatically reducing bisretinoid production over a lifetime. Our vermilion, rhodopsin-protecting spectral sunglasses should dramatically reduce bisretinoid production while allowing shorter wavelengths to detoxify accumulated lipofsucin. Recently two different aggressive pharmaceutical approaches to slow AMD and Stargardt's have been proposed to significantly reduce rhodopsin turnover by slowing the visual cycle, thereby create night blindness. Our vermillion sunglasses can achieve higher levels of protection when in bright sunlight while actually improving dark-adaptation and minimizing night blindness. Alternatively chronic photochemical stress in AMD and Stargardt's has been hypothesized to be related to oxidized bisretinoids and their creation of reactive oxygen species on exposure to violet-blue light. Previously we had designed and test blue-light absorbing sunglasses in moderate AMD patients. To directly evaluate these alternative hypotheses, we designed bicolored sunglasses in which one eye is provided a vermilion (green-blocking) filter that specifically protects rhodopsin and the other eye a yellow (blue-violet-blocking) filter that specifically protects from short-wavelength photochemical injury. When worn whenever in bright sunlight, such sunglasses allow us to compare changes in both eyes in which only spectral irradiance is changed while genetics, physiology and environmental exposures are otherwise the same. We have in conjunction with the NEI Eye Clinic developed clinical noninvasive, multispectral retinal autofluorescence imaging using both fundus cameras and confocal scanning laser ophthalmoscopes (CSLO) in order to directly map both the levels of fluorescent bisretinoids in human subjects and the local levels of rhodopsin within the photoreceptor layer. We have implemented new protocols using commercial cSLO autofluorescence imaging to map rhodopsin density and correlate that with the maps of absolute bisretinoid autofluorescence levels. We are seeking to relate changes in their levels with microscopic pathology progression in early age-related maculopathy and in Stargardts. Recently we have begun study of patients with reticular pseudodrusen in which RPE dysfunction in associated with accumulated drusenoid debris within the photoreceptor layer. We have developed a number of protocols for quantitatively mapping both RPE bisretinoid and rod rhodopsin levels based on autofluorescence imaging. Inverse correlations between local rhodopsin absorbance and underlying bisretinoids fluorescence at a given time point within these reticular drusen suggest mechanisms for the development of reticular drusen pathology. Serial measurements during successive yearly visits of these patients is currently being planned. Such studies of spatial temporal patterns of these molecular relationships in vivo in reticular drusen patients may lead to fundamental understanding of progression to geographic atrophy and visual loss in AMD and Stargardts. A critical factor in such image analysis is corrections for the optical effects of lens fluorescence, absorption and scattering and absorption and reflectivity of the retina, RPE and underlying choroid. We have refined optical models of these contributions and developing automatic computerized analyses of multispectral autofluorescent image sets to correct for background and consistently map macular pigment absorption in the photoreceptor axons above the autofluorescent RPE. We are using the local internal control of macular pigment distribution to validate our corrected multispectral image sets. We are currently working on analysis of these corrected multimodal image sets to identify and characterize microscopic retinal pathology changes and the effects of bisretinoid levels on their development. We plan to use these methodologies to test the effects of spectral photoprotection on steady state bisretinoid levels in normal retinal regions and in regions of early local RPE dysfunction as indicated by extracellular RPE-associated drusen. We are currently focusing on understanding the micropathology and progression of reticular pseudodrusen and the associated rod (rhodopsin) loss within them.